Osteoarthritis or degenerative joint disease is a slowly progressive, irreversible, often monoarticular disease characterized by pain and loss of function (Mankin and Brandt, Pathogenesis of Osteoarthritis in "Textbook of Rheumatology", Kelly, et al., (eds.) 3rd edition, W. B. Saunders Co., Philadelphia, pp.14699-111471) and Dean, Arth. Rheum. 20 (Suppl. 2):2 (1991)). The underlying cause of the pain and debilitation is the cartilage degradation that occurs as a result of the disease. A typical end-stage clinical picture includes complete erosion of the weight-bearing articular cartilage, requiring total joint replacement.
The pro-inflammatory cytokine interleukin-1 (IL-1) plays a major role in the cartilage matrix destructive processes observed in osteoarthritis (Pelletier, et al., Sem. Arth. Rheum., 20:12 (1991) and McDonnell, et al., Arth. Rheum., 35:799 (1992)). IL-1 has been demonstrated to upregulate the synthesis and secretion of the matrix metalloproteinases stromelysin and interstitial collagenase in a dose dependent manner (Stephenson, et al., Biochem. Biophys. Res. Comm. 144:583 (1987) and Lefebvre, et al., Biochem. Biophys. Res. Comm., 152:366 (1990). These matrix metalloproteinases are responsible for the damage to the proteoglycan and collagen II components of the cartilage matrix which occur in osteoarthritis (Dean, et al., J. Clin Invest., 84:678 (1989), Mort, et al., Matrix, 13:95 (1993) and Buttle, et al., Arth. Rheum., 12:1709 (1993).
Currently, there is no therapeutic approach available that will slow the clinical progression of osteoarthritis, although steroids and non-steroidal anti-inflammatory drugs are used to ameliorate the pain and inflammation associated with the disease. Consequently, there is a need for new therapeutics which slow the joint degeneration caused by osteoarthritis.